ITOR Translational Research: A History of Conducting First in Man Trials
First In Man Trials Background
A first-in-man study is a clinical trial where a medical procedure, previously developed and assessed through in vitro or animal testing, is tested on human subjects for the first time. These studies are designed to speed up the development of promising drugs by establishing very early in the process whether or not the drug or agent behaves in human subjects as was expected from preclinical studies - and whether or not it is safe to undergo further development. The ITOR Clinical Research Unit (CRU) has conducted clinical trials where compounds were administered to the first human subjects worldwide.
First In Human Trials conducted by ITOR's Clinical Research Unit, include the following:
- Intravesical CG0070 with DDM washing for Transitional Cell Carcinoma of the Bladder
CG0070 is a conditionally replicating oncolytic adenovirus regulated by a promoter up-regulated in Rb pathway defective tumor cells. It selectively expresses GM-CSF. - Seneca Valley Virus (SVV-001) for Neuroendocrine Solid Tumors
SVV-001 is a replication competent picornavirus. - AZD4877 for Advanced Solid Tumors
AZD4877 is an Eg5 inhibitor. Inhibition of Eg5 leads to cell death through the formation of a monopolar spindle (monoaster), arresting cells in mitosis. - CG53135 for Chemotherapy Induced Mucositis/Stomatitis
CG53135 is a fibroblast growth factor that induces proliferation of epithelial and mesenchymal cells. - Dendrivax for Renal Cell Carcinoma
Vaccine created by fusing autologous dendritic cells with irradiated tumor cells and given in conjunction with IL-2. - Melanix® Vaccine for Melanoma
Dendritic cells fused with irradiated tumor cells as a cancer vaccine in conjunction with BCG. - JX594 for Advanced Solid Tumors
JX594 is a replication-competent, GM-CSF transgene-expressing therapeutic vaccinia virus. - Tokai-001 in Castration Resistant Prostate cancer:
Inhibits CYP17, an enzyme that controls androgen production in the adrenals, testes and prostate; binds to the AR receptor.
Decreases the amount of AR protein within the cancer cell and diminishes the ability of the cell to be sustained by low levels of androgens. - E7106 in Solid Tumors
E7016 is PARP inhibitor. Poly(ADP-ribose) polymerase (PARP) is an abundant nuclear enzyme that mediates repair of DNA single-strand breaks via the activation and recruitment of DNA repair enzymes through synthesizing poly(ADP-ribose) from nicotinamide adenine dinucleotide (NAD).
ITOR Biosafety Level II - Gene Transfer Therapy Trials
In addition to the signature history of the Institute for Translational Oncology Research (ITOR) of Greenville Health System (GHS) in First In Human Studies, the ITOR Clinical Research Unit also conducts gene transfer therapy on an ongoing basis.
Background
Gene therapy is a technique for correcting defective genes responsible for disease development. Researchers may use one of several approaches for correcting faulty genes:
- A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene (This being the most common approach).
- An abnormal gene can be swapped for a normal gene through homologous recombination.
- An abnormal gene can be repaired through selective reverse mutation, returning the gene to its normal function.
- The regulation of a particular gene (the degree to which a gene is turned on or off) can be altered.
Biosafety Level II Gene Transfer Therapy Trials
The ITOR Clinical Research Unit has conducted multiple gene transfer therapies, including the following:
- TNFerade Plus Radiation in Patients with Advanced Melanoma
TNFerade is a non-replicating adenovirus ligated upstream from human TNF transgene allowing maximum gene expression in presence of ionizing radiation and is given as an intratumoral injection into subcutaneous lesions. - TNFerade Biologic with 5FU and XRT as First Line Therapy for Locally Advanced, Unresectable Pancreatic Cancer
TNF transgene allowing maximum gene expression in presence of ionizing radiation and is given as a CT guided intratumoral injection. - Intravesical CG0070 with *DDM washing for Transitional Cell Carcinoma of the Bladder
CG0070 is a conditionally replicating oncolytic adenovirus regulated by a promoter upregulated in Rb pathway defective tumor cells. It selectively expresses GM-CSF. - GI4000/Placebo + Gemcitabine for Completely Resected Pancreatic Cancer
GI4000 is a recombinant heat inactivated yeast engineered to express one of three mutated Ras oncoproteins. - Taxotere plus GVAX versus Taxotere/Prednisone for Hormone Refractory Chemo Naïve Metastatic Prostate Cancer
CG1940 and CG8711 are components of a prostate adenocarcinoma cell line genetically modified to secrete GM-CSF into tumor cells ex vivo using a recombinant adeno-associated viral vector. - Lucanix as Maintenance Therapy for Stage III/IV NSCLC with Stable Disease or Response Following Front-Line Platinum Based Therapy
Lucanix is an allogeneic vaccine cocktail modified with a TGF-β2 antisense vector. - Seneca Valley Virus (SVV-001) for Neuroendocrine Solid Tumors
SVV-001 is a replication competent picornavirus. - JX594 for Metastatic Melanoma
JX594 is a replication-competent, GM-CSF transgene-expressing therapeutic vaccinia virus given as an intratumoral injection. - JX594 for Advanced Solid Tumors
JX594 is a replication-competent, GM-CSF transgene-expressing therapeutic vaccinia virus given intravenously.
ITOR Translational Research in Conjunction with Highlighted Innovation Partners & Collaborators
Private Sector Research Collaborations
Senex Biotechnology, Inc.
Senex Biotechnology® is a drug discovery company dedicated to becoming the world's leading company that targets a signaling pathway activated by cellular damage and involved in cell senescence (aging). This Cyclin-dependent Kinase Inhibitor (CKI) pathway plays an important role in cancer.
In collaboration with Senex, physicians and staff of the ITOR CRU have been instrumental in supporting a funding opportunity through the NIH focused on accelerating the development of cancer therapeutics, imaging technologies, interventional devices, diagnostics, and prognostics toward commercialization. The primary objective is to bring SNX2, a CKI, into clinical testing in 2011.
Selah Technologies (A Research Division of Lab 21)
Breast Cancer Initiative
In collaboration with Selah Technologies, the ITOR Biorepository staff is assisting on the clinical front by obtaining patient's permission to collect excess tissue obtained at the time of routine cancer surgeries or biopsies. The overall objective of this study is to demonstrate the technical feasibility of using brightly photoluminescent Selah Dots® coupled to a model biomarker to selectively image breast cancer cells ex vivo. This is a proof of concept study.
Oncolix Drug Development Initiative - Prolanta
Oncolix is currently working with researchers at the Clemson University Biomedical Institute located at the Greenville Health System in Greenville, SC, and with M.D. Anderson Cancer Center in Houston, TX. The primary goal is to conduct preclinical studies to evaluate the effect of Prolanta on cancer stem cells and ovarian cancer, and to test Prolanta in combination with other anticancer agents used to treat breast and ovarian cancer.
The ITOR Clinical Research Unit will be involved with the first clinical trial of Prolanta in metastatic breast cancer, which is anticipated to begin in Q4 2010.
Prolanta is a variant of normal human hormone prolactin (PRL) in which the single glycine amino acid at position 129 has been substituted with arginine. With this modification of the PRL molecule, Prolanta blocks PRL's action by preventing it from binding to the PRL receptor (PRLR). PRL is a peptide hormone associated with mammary gland development and lactation and development of the ovaries. PRL is synthesized and secreted mainly by lactotroph cells in the anterior pituitary gland. When PRL binds to the PRLR, it causes it to dimerize with another receptor and activate the JAK-STAT intracellular pathway. This pathway plays a central role in cell fate decisions, such as cell proliferation, differentiation and apoptosis.
ITOR Research University Initiatives
The Institute for Translational Oncology Research is committed to ongoing collaboration with research university partners, serving as a vital clinical test bed and translational research laboratory for basic scientists and academic researchers - in a mutual quest to rapidly transfer basic science data and discovery into meaningful clinical benefit.
One of the primary goals is to jointly develop and create new breakthroughs in rapid drug development and accompanying diagnostic discovery - including genomic profiling of cancer tumors and the design of clinical trials utilizing known targets that are expressed, versus disease specific, in order to achieve true personalized medicine - ultimately advancing cancer care for patients.
For additional information about ITOR of GHS Research University collaborative initiatives, please link to the following institutions (which are profiled within the ITOR Collaborators web section):
ITOR Federal Government Research Initiatives
The Institute for Translational Oncology Research and its consortia of research university and private sector partners continues to explore and develop vital research relationships with key federal government agencies and institutes - including the NCI, the NIH, the Department of Defense, and beyond.
Several innovative initiatives are being actively explored, and numerous grant proposals are currently in the translational research pipeline.
Areas of interest range from advances in breast cancer diagnosis to the development of unique research and clinical delivery models in relation to biorepository services, gene sequencing, and molecular validation.